My clinical and translational program is focused on targeting of the DNA repair and related pathways for therapeutic potential in recurrent ovarian cancer through investigator-initiated clinical trials and biomarker analysis. My lab efforts are aimed at investigating novel therapeutic combinations in HGSOC, focused on targeting key proteins in the DNA repair and cell cycle pathways. These preclinical projects will provide the ability to move rapidly into the hypothesis-driven clinical trials of the combination of the different pathway regulators in recurrent ovarian cancer. Project #1: Therapeutic modulation of cell cycle checkpoint pathways in women's cancer. Cell cycle checkpoint kinase 1 and 2 (CHK1/2) are major regulators of the cell cycle and are intimately associated with the cellular response to DNA damage and repair. CHK1/2 functions as the primary mediator of cell-cycle arrest in tumors with dysfunctional TP53, such as HGSOC. I hypothesize that a CHK1/2 inhibitor (CHK1/2i) will induce lethal DNA damage and resultant clinical activity in recurrent HGSOC patients. I have developed and opened a phase II investigator-initiated study of the second generation CHK1/2 inhibitor, prexasertib (LY2606368, 14-C-0156) in HGSOC patients with and without germline BRCA mutation. We continue to enroll Cohort 1 BRCA mutated HGSOC patients. We completed accrual of HGSOC patients without germline BRCA mutation (Cohort 2), and observed the promising activity of prexasertib monotherapy in heavily pre-treated recurrent platinum-resistant BRCA wild type HGSOC patients (a response rate of 33%). Our findings from Cohort 2 were recently published in Lancet Oncol. Also, our results led to the development of recently opened global phase II trial and possible phase III registration trial for this patient population. This study incorporates tumor biopsies and blood collections, genomic analyses and other molecular investigations to identify mechanisms of sensitivity, and to better define the subsets that respond to therapy, which have not clinically been examined in HGSOC. Correlative study endpoints evaluation is currently ongoing. I opened the two cohorts (biopsy Cohort 5 and non-biopsy Cohort 6) of recurrent platinum-resistant HGSOC within the 14-C-0156 study to further confirm clinical activity of prexasertib in this patient population and also to investigate de novo and acquired clinical resistance mechanisms. These cohorts incorporates mandatory pre-treatment and at progression tumor biopsies and blood collections. To capitalize and expand on the benefits of prexasertib, I am combining targeted agents with prexasertib to enhance response rates in recurrent HGSOC. My group examined the cytotoxic effect of a PARP inhibitor, olaparib and prexasertib preclinically in HGSOC cells. Our finding was recently published in Oncotarget. To develop the next generation of clinical trials (e.g., combinations that might increase the activity of prexasertib), I collaborated with Dr. C. Thomas using a quantitative high throughput screening approach developed by the NCATS that enables the discovery of synergistic drug combinations. In the screen, several inhibitors of PI3K family, AKT and mTOR pathways induced at least additive cytotoxic activity with prexasertib. My lab first validated findings from NCATS screening in a panel of p53 mutant HGSOC cell lines. While conducting further mechanistic preclinical work using prexasertib and LY3023414 (PI3K/mTOR inhibitor), I also wrote a protocol for the new investigator-initiated phase II trial of prexasertib and LY3023414 combination which is now under review and CRADA negotiation with Eli Lilly. Lastly, although prexasertib showed promising single agent activity in recurrent HGSOC, the patients eventually progress on the treatment. Potential resistance mechanisms of the cell cycle checkpoint inhibition are not well studied. My group is in collaboration with Dr. Steeg's Lab and Dr. Pommier's Lab to understand de novo and acquired resistance mechanisms of prexasertib and/or other cell cycle inhibitors in HGSOC. Project #2: Therapeutic strategies to complement immune checkpoint inhibition. Immunotherapy has emerged as a major therapeutic modality in oncology, yet most patients with ovarian cancer do not derive benefit from immune checkpoint blockade monotherapy, suggesting the need to develop and test rational combination strategies. Inhibition of DNA repair and angiogenesis pathways can modulate immune response by increasing DNA damage and tumor mutational burden and by attenuating immunosuppressive microenvironment. Olaparib and cediranib together were shown to be clinically superior to olaparib alone in recurrent platinum-sensitive ovarian cancer patients, suggesting an important new direction for immune checkpoint blockade combination therapy. I hypothesize that the PARP inhibitor olaparib and a VEGFR1-3 inhibitor cediranib will enhance the anti-tumor activity of immune checkpoint blockade, by creating higher mutational loads and a more immunogenic environment. I have developed and opened a phase I/II investigator-initiated study (15-C-0145), which tests this hypothesis by combining the PD-L1 inhibitor, durvalumab (MEDI4736) with a PARP inhibitor, olaparib or a VEGFR inhibitor, cediranib. My phase I findings, the first of these combination approaches, were published in JCO, showing tolerability and activity of the combinations at and below the recommended phase 2 doses of the two doublets (durvalumab plus olaparib or cediranib). Also, phase I findings of triplet therapy (durvalumab plus olaparib and cediranib) were presented at the 2017 ESMO meeting. Phase II studies with biomarker analysis in HGSOC and triple negative breast cancer are currently ongoing. This clinical trial has been expanded to bring these therapeutic opportunities and translational research approaches to other tumor types such as metastatic castrate resistant prostate cancer. Early clinical findings from a prostate cancer cohort demonstrated promising activity in heavily pretreated patients. Project #3: Therapeutic targeting the key proteins of DNA repair and angiogenesis pathways in recurrent HGSOC patients. Angiogenesis and DNA damage repair pathways are active and interactive therapeutic targets in recurrent HGSOC. I hypothesized optimal targeting of PARP and VEGF/VEGFR pathways will yield improved clinical outcome in recurrent HGSOC patients. We reported a multi-institutional randomized phase II study of the combination of olaparib and cediranib in platinum-sensitive recurrent ovarian cancer, which showed a remarkable prolongation of progression free survival with the combination compared to olaparib alone (12-C-0081/J-M Lee: the translational science PI). This newly uncovered anti-tumor activity of the combination led to development of the two NRG Oncology international trials (opened in April 2016) of olaparib and cediranib in platinum-resistant (PI: J-M Lee, a late phase II/III study, NRG GY005 [16-C-0088]) and platinum-sensitive recurrent ovarian cancer (PI: J Liu; a phase III study, NRG GY004). I have developed this clinical trial, through CTEP, NRG (NSABP-RTOG-GOG) Oncology and have worked with intramural and extramural experts in successful clinical and translational collaborations. NRG GY005 study has enrolled a target accrual of 208 patients for a phase II part and phase III part will reopen in 4Q 2018 in the United States, Canada, Japan and South Korea. The correlative endpoints built into this trial will further our understanding of the DNA repair and angiogenesis pathways modulation by targeted agents and lead to the next generation of pathway combinations for recurrent HGSOC patients.